Effect of hepatic FPN ablation on the liver transcriptome in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE292556 | GEO | 2026/04/14
REPOSITORIES: GEO
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Project description:Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin (Hamp), a hepatic-derived hormone that controls iron mobilization through its molecular target, ferroportin (FPN), the only known mammalian iron exporter. Here, we took a transcriptomic approach to to compare the duodenal transcriptome during systemic iron demand to that of hepcidin-deficiency iron overload. Hampfl/fl (control) and AlbCreERT2;Hampfl/fl mice were placed on iron-replete and low-iron diets and were sacrificed two weeks following tamoxifen treatment. Duodenum RNA expression was compared across genotypes and across iron-replete and low iron diets.
2018-12-12 | E-MTAB-7329 | biostudies-arrayexpress
Project description:Aging drives systemic metabolic dysfunction (SMD) and increases the risk of chronic illnesses such as metabolic dysfunction–associated steatotic liver disease (MASLD) and chronic kidney disease (CKD). However, mechanisms that connect aging to multi-organ deterioration are poorly understood. In this study, we identify hepatocyte Hedgehog signaling as a central regulator of ferroptosis. Using mice with hepatocyte-specific deletion of Smoothened (Smo), a key Hedgehog pathway component, we show that loss of hepatocyte Hedgehog signaling induces ferroptotic stress, lipid peroxidation, and cellular senescence. These changes were sufficient to cause spontaneous MASLD and to trigger secondary kidney injury. Smo deletion also disrupted systemic iron balance, increased hepatocyte production of the angiotensinogen, and reduced liver perfusion. Similar responses (iron dysregulation, vascular dysfunction, and reduced Hedgehog signaling) were observed in patients with MASLD and advanced fibrosis. Inhibition of ferroptosis with ferrostatin-1 reversed hepatocyte senescence, restored hepatic blood flow, and improved both liver and kidney injury in Smo-deficient mice. Overall, these findings show that hepatocyte Hedgehog signaling preserves liver homeostasis by restraining ferroptotic stress and coordinating iron-dependent vasoactive pathways. The results reveal an unrecognized aging-related communication axis between liver and kidney and identify the Hedgehog–ferroptosis pathway as a promising therapeutic target for age-associated metabolic diseases.
2026-05-08 | GSE330266 | GEO
Project description:Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinson’s disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients
2015-03-11 | GSE66730 | GEO
Project description:Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinson’s disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients Using Ribotag technology, from mouse ventral midbrain lysates, we isolated actively translated mRNA species from control and Transferrin receptor 1-null dopaminergic neurons. Two mouse ages were used 3 wks (early neurodegeration) 10 wks (late neurodegeneration)
2015-03-11 | E-GEOD-66730 | biostudies-arrayexpress
Project description:SLC40A1 (also known as ferroportin) is a key iron exporter that maintains intracellular iron homeostasis and regulates macrophage function. In this study, we found that a metabolically reprogrammed SLC40A1+ subset of tumor-associated macrophages (TAMs), characterized by ferroptosis resistance and immunosuppressive features, is enriched in patients who do not respond to PD-1 immune checkpoint blockade therapy. To further investigate the regulatory role of SLC40A1 in macrophage immune function and ferroptosis resistance, we performed RNA sequencing on differentiated THP-1 macrophages transfected with either SLC40A1-targeting siRNA or negative control siRNA.
2025-07-15 | GSE302068 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD), closely associated with obesity, can progress to metabolic dysfunction-associated steatohepatitis when the liver undergoes overt inflammatory damage. A-kinase anchoring protein 1 (AKAP1) has been shown to control lipid accumulation in brown adipocytes. However, the role of AKAP1 signaling in hepatic lipid metabolism and MASLD remains poorly understood. Here, we showed that hepatocyte-specific AKAP1 deficiency exacerbated hepatic steatosis and steatohepatitis in male mice subjected to a high-fat diet and fast-food diet, respectively. Mechanistically, AKAP1 directly phosphorylated and inactivated glycerol-3-phosphate acyltransferase 1 (GPAT1) in a PKA-dependent manner, thus suppressing lysophosphatidic acid (LPA) production. Increased endogenous LPA in hepatocytes promoted hepatocellular triglyceride (TG) synthesis and initiated pronounced inflammatory response in Kupffer cells. Restoring hepatic AKAP1 or repressing LPA levels via GPAT1 knockdown alleviated MASLD exacerbation. Overall, AKAP1 plays a protective role against MASLD by inhibiting GPAT1 activity, highlighting the potential of targeting AKAP1/PKA/GPAT1 signalosome for MASLD therapy.
2025-05-26 | PXD062388 | Pride
Project description:Aberrant iron metabolism is considered to be a risk factor for the exacerbation of chronic liver disease. Recently, increasing evidence points out the contribution of iron to epigenetic regulation in several biological contexts. However, the involvement of iron-mediated epigenetic regulation in the progression of chronic liver disease is unknown. To investigate the impact of iron on hepatocyte epigenetics during the progression of chronic liver disease, mice with genetic iron overload in the liver (Alb-Cre/FBXL5F/F) were fed with a cholestasis-inducing diet (0.1% DDC diet). Hepatocytes were isolated from the diseased livers of Alb-Cre/FBXL5F/F and FBXL5F/F mice and subjected to ATAC-seq. Chromatin accessibility of several genes including chemokines was altered in hepatocytes of Alb-Cre/FBXL5F/F mice in comparison to those of FBXL5F/F mice, suggesting that iron participates in the fine-tuning of hepatocyte epigenetics in chronic liver disease.
2026-03-31 | GSE284304 | GEO
Project description:Adipose tissue dysfunction drives hepatic lipid overload in metabolic dysfunction-associated steatotic liver disease (MASLD), yet the involvement of adipose tissue-derived small extracellular vesicles (sEVs) remains unclear. Herein, we showed that transplanting adipose tissue from high‑fat diet-fed male mice exacerbated insulin resistance and hepatic steatosis in lean recipients. Adipose‑specific Sirt3 overexpression (Sirt3AKI) alleviated insulin resistance and liver steatosis in high fat diet-fed male mice, whereas adipose‑specific Sirt3 knockdown aggravated these phenotypes. Moreover, adipose‑derived sEVs play key roles in hepatic lipid metabolism by delivering miRNAs in Sirt3AKI male mice. MicroRNA sequencing identified miR-30a-3p was increased in the circulating sEVs from high fat diet-fed male mice, while decreased in sEVs from Sirt3OE adipocytes and Sirt3AKI male mice. Mechanistically, miR‑30a‑3p promoted hepatic steatosis by targeting Becn1; this process was suppressed when Sirt3 downregulated miR‑30a‑3p transcription via deacetylation of H3K56. These findings highlight the critical role of adipose sEVs microRNAs in driving hepatocyte lipotoxicity, and suggest miR-30a-3p inhibition could be a therapeutic intervention for MASLD.
2026-03-17 | GSE325068 | GEO
Project description:The liver is the central organ critically regulating the balance of the metabolically potent yet toxic bile acids in the body. While genomic association studies have pointed to hepatic Sel1L – a critical component of mammalian Hrd1 ER-associated degradation (ERAD) machinery – as an influencer of serum bile acid levels, physiological relevance and mechanistic insights of ERAD in bile homeostasis remain unexplored. Using hepatocyte-specific Sel1L-deficient mouse models, we report that hepatic Sel1L-Hrd1 ERAD critically manages bile homeostasis in the body. Mice with hepatocyte-specific Sel1L developed intrahepatic cholestasis, with significant overload of bile acids in the liver and circulation under basal condition, and were hypersensitive to dietary bile acid challenge. By contrast, biliary bile acid and phosphatidylcholine levels were reduced, pointing to an export defect from hepatocytes. Unbiased proteomics analysis followed by biochemical assays revealed significant accumulation of the bile-stabilizing phosphatidylcholine exporter ATP-binding cassette 4 (Abcb4) in the ER of Sel1L-deficient livers, a gene associated with Progressive Familial Intrahepatic Cholestasis type III. Indeed, Abcb4 was a substrate of Sel1L-Hrd1 ERAD. Hence, hepatic Sel1L-Hrd1 ERAD maintains bile equilibrium via quality control of Abcb4 maturation in the ER.
2023-03-11 | PXD035243 | Pride
Project description:Iron withholding controls infections by limiting the pathogens’ access to iron from the host. Viruses directly utilize intracellular materials, including iron, to complete their life cycles. Emerging evidence suggests the importance of withholding iron in limiting viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense remain unknown. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses.
2025-01-01 | GSE280144 | GEO